Objective: To test the a priori hypothesis that longer duration of ruptured membranes is associated with increased risk of vertical transmission of HIV.Design: The relationship between duration of ruptured membranes and vertical transmission of HIV was evaluated in an individual patient data meta-analysis.Methods: Eligible studies were prospective cohort studies including at least 100 mother-child pairs, from regions where HIV-infected women are counselled not to breastfeed. Analyses were restricted to vaginal deliveries and non-elective Cesarean sections; elective Cesarean section deliveries (those performed before onset of labour and before rupture of membranes) were excluded.Results: The primary analysis included 4721 deliveries with duration of ruptured membranes less than or equal to 24 h. After adjusting for other factors known to be associated with vertical transmission using logistic regression analysis to assess the strength of the relationship, the risk of vertical HIV transmission increased approximately 2% with an increase of 1 h in the duration of ruptured membranes [adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.04; for each 1 h increment]. There were no significant interactions of duration of ruptured membranes with study cohort or with any of the covariates, except maternal AIDS. Among women diagnosed with AIDS, the estimated probability of transmission increased from 8% to 31% with duration of ruptured membranes of 2 h and 24 h respectively (P < 0.01).Conclusions: These results support the importance of duration of ruptured membranes as a risk factor for vertical transmission of HIV and suggest that a diagnosis of AIDS in the mother at the time of delivery may potentiate the effect of duration of ruptured membranes. (C) 2001 Lippincott Williams & Wilkins.

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

The influence of host immunogenetics on the outcome of vertically transmitted HIV infection in children was examined in a multicenter cross sectional study of long term survivors and rapid progressors. Sequence-based typing was performed for the DRB1, DQB1 and HLA-A loci. 36.7% of 30 children surviving more than 8 years had one or more of the HLA-DR13 alleles, versus none of 14 rapidly progressing children who died within 2 years of age, p = 0.009, Haldane RR = 17.1. The alleles variably associated with this beneficial response to HIV were: DRB1*1301, DRB1*1302, DRB1*1303 and DRB1*1310, suggesting that the DR13 effect acted as a dominant trait. An additional 6 children were typed only by the SSOP method resulting in 44.4% of 36 long term surviving children with a DR13 allele and none of 14 rapid progressors, p = 0.002, Haldane RR = 23.3. No single DQB1 allele accounted for the HLA-DR13 allele association. In contrast, the presence of HLA A*2301 was associated with rapid progression to AIDS, 4% of long term survivors vs. 57.1% of 7 rapid progressors, p = 0.0006, RR = 0.031. Although the sample size is small, the marked differences in allele frequency along with differences between the peptide binding pockets of the HLA-A9 group of alleles including HLA A*2301 and the remainder of the HLA-A alleles suggest a structural basis for the dominant disadvantageous immune response to HIV conferred by A*2301.

Worldwide clinical trials are in progress or are being planned to evaluate different interventions aimed at reducing transmission of human immunodeficiency virus (HIV) from mother to infant. Several new therapeutic agents will soon be the focus of clinical trials to evaluate their safety for pregnant women and their infants and to test their efficacy in preventing perinatal transmission. Identification of the factors that influence the timing and mechanism of perinatal HIV transmission is essential to the assessment of interventions to reduce transmission. An international workshop was held on June 3-6, 1993, in Siena, Italy, to review what is known about the risk factors, timing, and mechanisms of HIV type 1 (HIV-1) transmission from mother to infant during gestation, birth, and lactation. Several possible interventions were compared with respect to their mechanism of action, their dependence upon the mode and timing of perinatal HIV transmission, and their suitability for incorporation into trials, alone or in combination, in various parts of the world. Obstetrical interventions such as caesarian section or use of a virucidal vaginal lavage during labor, administration of antiretroviral drugs to mother and/or infant, as well as active and/or passive immunization were discussed. The role of breast-feeding in perinatal HIV infection and in the trials was also evaluated. Because the ability to enroll pregnant, HIV-infected women in trials is limited, it is essential that proposed trials be carefully evaluated for adequacy of the sample size, appropriateness of the type of intervention to the particular population of women to be enrolled, and feasibility of the intervention. Worldwide coordination of perinatal intervention trials is essential to prevent duplication, allow the optimal use of human and financial resources, and ensure the most rapid possible evaluation and implementation of means to prevent pediatric HIV infection.

To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 mug/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 mug/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.

CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains 4 extracellular sequences homologous to Ig variable domains, the first of which (V1) is sufficient for binding to HIV. To develop CD4 as an anti-HIV therapeutic, we engineered a CD4 immunoadhesin (CD4-IgG)--a fusion protein containing the V1 and V2 domains of CD4 with the hinge and Fc regions of human Ig heavy chain. A chimeric protein of this type has several advantages compared to the soluble receptor, including a greatly extended in vivo half-life and greater avidity for HIV; moreover, like an antibody, it performs effector functions via its Fc domains, such as complement activation and antibody-dependent cell-mediated cytotoxicity. In vivo experiments show that CD4-IgG protects against HIV-I IIIB infection of chimpanzees when administered prior to viral challenge. In addition, CD4-IgG is transferred efficiently across the placenta from mother to fetus in rhesus monkeys. To evaluate its safety in humans, we conducted a phase-I clinical trial in adult patients with AIDS and AIDS-related complex. We found that, in a total of 16 patients, administration of CD4-IgG was well tolerated at doses up to 1000 micrograms/kg of body weight, with no important clinical or immunological toxicities noted. Given its unique properties, particularly the ability of CD4-IgG to cross the placenta, we plan to focus future clinical efforts on preventing infection of newborns via maternal-fetal transfer of HIV.

To evaluate the immunogenicity of purified recombinant envelope glycoprotein of HIV-1 (rgp120) as a potential vaccine for AIDS, the antibody response of 45 baboons to rgp120 was investigated using an adjuvant (alum) and route of administration (intramuscular) suitable for humans. The primary purpose was to evaluate the effects of different doses and immunization schedules on the antibody response to rgp120 in primates. A secondary objective was to evaluate possible adverse consequences of rgp120 immunization. A liquid-phase radioimmunoprecipitation (RIP) assay for detection of rgp120-reactive antibodies revealed that rgp120 doses of 30-300 micrograms per administration resulted in nearly indistinguishable serum antibody responses. However, significant enhancement of serum antibody titers was observed when the interval between the second and third administrations was increased from 4 to 20 w. Although changing the interval significantly altered the magnitude of resulting peak titers, the kinetics of antibody formation were not changed. Thus, of the three schedules of immunization tested, none resulted in a sustained humoral immune response. The significance of the RIP assay for evaluating immune responses was confirmed by analysis showing that the percentage of immunized baboons that developed in vitro HIV-1 serum neutralizing responses was greatest in groups that also exhibited high anti-rgp120 RIP titers. Immunization with rgp120 had no significant adverse effect on any clinical or laboratory parameter monitored over the course of the study.